The clinical management of numerous neurological disorders has been frustrated by the progressive nature of degenerative, traumatic, or destructive neurological diseases and the limited efficacy and serious side-effects of available pharmacological agents. Conditions such as Huntington's disease, Alzheimer's disease, severe seizure disorders (e.g., epilepsy and familial dysautonomia), as well as injury or trauma to the nervous system have eluded most conventional pharmacological attempts to alleviate or cure the conditions.
Huntington's disease has proven particularly elusive to conventional pharmacological treatments. Huntington's disease is a progressive degenerative disease of the basal ganglia that is inherited as an autosomal dominant trait. The onset of Huntington's disease, an autosomal dominant, neurodegenerative disorder occurs at an average age of 35 to 40 years but can occur in persons as young as two years old or as old as 80 years (Scientific American, Medicine, Dale & Federman, eds. Vol. 3, 11(XV), p. 12-13 [1997]9(IV), p. 29 [1996]). The onset is insidious and is characterized by abnormalities of coordination, movement, and behavior. Movement abnormalities include restlessness, mild postural abnormalities, and quick jerking movements of the fingers, limbs, and trunk. The movement abnormalities may be accompanied by substantial weight loss. Depression is common, and cognitive abnormalities and inappropriate behavior may develop. In contrast to the choreic movements typical of onset in adults, juvenile patients may exhibit rigidity, tremor, and dystonia. In the course of eight to 15 years, the disorder progresses to complete incapacitation, with most patients dying of aspiration pneumonia or inanition.
In 1983, Huntington's disease became the first major inherited disorder with an unidentified basic defect to be linked with a DNA marker (Gusella et al., Nature 306:234 [1983]). The product of this gene, designated huntingtin, contains more than 3000 amino acids and is encoded by 10,366 bases at 4p16.3 (Huntington's Disease Collaborative Research Group, Cell 72:971 [1993]). Although knowledge of the underlying molecular basis for Huntington's disease has increased in recent years, pharmacological treatments based on this molecular knowledge have been limited to alleviating some of the symptoms associated with HD, a procedure that does not address the primary degenerative process nor the nonmotor aspects of the disease.
Cell therapy presents an alternative to these ineffective conventional pharmacological strategies for the treatment of neurological diseases. The goal of cell therapy is to replace, repair, or enhance biological function in damaged or deficient tissues or organs. Cell therapy is accomplished by the transplantation of isolated and characterized cells into a target tissue or organ in sufficient number and quality to restore or impart the desired function. Cell therapy, thus, provides a means of treating disorders where whole or partial organ transplantation is not practical or possible.
Cell transplantation methods have been of particular interest in the treatment of neurological diseases. However, mature neural tissues cannot be used for neural cell transplantation. Such tissues are not capable of surviving or establishing neurological function, which often depends on complex intercellular connections that cannot be surgically established. Thus, it is clear that improved methods and compositions are needed for the effective treatment of neurological diseases.